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1.
Front Pharmacol ; 13: 912688, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35814251

RESUMO

Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies. Rheb activates mTORC1 in the cytosolic surface of lysosomal membranes. Rheb's farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDEδ. Recently, the use of PDEδ inhibitors has been proposed as anticancer agents because they interrupted KRas signaling leading to antiproliferative effects in KRas-dependent pancreatic cancer cells. However, the effect of PDEδ inhibition on the Rheb/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDEδ inhibitor, called Deltasonamide 1, in Tsc2-null MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDEδ interaction. Accordingly, we found that Deltasonamide 1 reduces mTORC1 targets activation. In addition, our results showed that Deltasonamide 1 has antiproliferative and cytotoxic effects on Tsc2-null MEFs but has less effect on Tsc2-wild type MEFs viability. This work proposes the pharmacological PDEδ inhibition as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells.

2.
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1385840

RESUMO

RESUMEN: A pesar de que los procesos epigenéticos son estudiados ampliamente de forma general, no se habían relacionado, hasta ahora, a las alteraciones genéticas más tradicionales asociadas en la etiopatogenia del cáncer oral. La visión de carcinogénesis tradicional y la de la epigenética convergen en las mismas vías moleculares involucradas en el desarrollo del cáncer, potenciándose durante el proceso de carcinogénesis oral. A continuación se realizará una revisón de las siguientes vías moleculares VEGF-C /VEGFR; HB-EGF /EGFR; Wnt /B-catenina y las ciclinas, desde un punto de vista genético y epigenético para establecer su conexión durante el proceso de carcinogénesis oral.


ABSTRACT: Although epigenetic processes are widely studied, no one has related them to the classical genetic processes in oral cancer etiopathogenesis. The traditional carcinogenesis and epigenetic views converge in the same molecular pathways involved in cancer development, enhancing this process. This review will approach the VEGF-C/VEGFR, HB-EGF/EGFR, Wnt /B-catenin, and cyclins molecular pathways from the genetic and epigenetic views to establish their connection during the oral cancer process.

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